ROLE OF EPIDERMAL GROWTH FACTOR RECEPTORS IN SIGNAL TRANSDUCTION AND TUMORIGENESIS

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Signalling through the epidermal growth factor receptor (EGFR) controls normal growth and differentiation of epithelial tissues through protein and lipid signal transduction pathways. EGFR signal transduction is initiated by ligand binding, receptor dimerization and inter-and intra-receptor activation of kinase activity, concomitant with phosphorylation of tyrosine residues on the EGFR. This activates downstream signalling pathways, including the mitogen-activated protein (MAP) kinases which ultimately phosphorylate a number of cytoplasmic substrates. This presentation will focus on basic properties of EGFR, effects of overexpression and tumorigenesis, possible mechanisms of drug resistance associated with overexpression of EGFR and possible strategies for blocking its expression in human tumors. Activation of proto-oncogenes may mediate transformation by overwhelming normal cellular control of these signaling cascades. The EGFR gene (c-erbB-1) is amplified and over-expressed in human malignant cells and structural rearrangements also occur. A truncated mutant of EGFR (EGFRvIII) expressed in human tumor cells lacks a portion of the EGFR binding domain. The mutant receptor exhibits elevated receptor autophosphorylation and spontaneous homodimerization. Expression of EGFRvIII induces morphological transformation in cell and animal systems. EGFRvIII has been expressed in fibroblast systems leading to cell transformation and formation of tumors when infected into nude mice. Fibroblasts containing normal EGFR or EGFRvIII in culture provide a useful model for study of intracellular signalling events potentially important in the transformation from normal to tumor cells. Expression of EGFRvIII in fibroblasts is associated with downstream activation of MAP kinase as evidenced by activation of cytoplasmic phospholipase A2 at levels similar to that induced by the intact EGFR. Chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal in cells. Other studies suggest that phosphoinositide 3-kinase may have an essential role in transformation by this mutant EGFR. Using mutant-specific antibodies and PCR it has been shown that EGFRvIII is present in human brain, breast, lung and ovarian tumors, but is absent in normal tissue. Oncogenic transformation confers resistance to chemotherapy, e.g. to taxanes. One mechanism under study is differential expression of β-tubulin isotypes which may modulate paclitaxel resistance. Expression of EGFRvIII appears to be specifically associated with paclitaxel resistance and elevated levels of tubulin type IVb RNA in cells transformed by this receptor. Current investigations focus on blockade of EGFRvIII by using tyrosine kinase inhibitors and monoclonal antibodies. This approach may be useful for blocking growth of human tumors.
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